1033: Obesity-induced epigenetic changes associated with adverse perinatal outcomes

Abstract

Maternal obesity is associated with higher risk of fetal/neonatal mortality and morbidity. We aim to determine if maternal obesity alters major epigenetic modifications, DNA and RNA methylation, by affecting gene expression of methylation writers and erasers in the placenta. A cross-sectional study included maternal-fetal dyads presenting for scheduled cesarean delivery. Unlabored women at 37 weeks gestation or greater, with non-anomalous singleton pregnancy were enrolled if they had no maternal risk factors for placental diseases. Classified by prepregnancy BMI, two groups of women were eligible: 18.5 to 24.9 (non-obese) and greater than 30.0 (obese). Any medical complications of pregnancy, concern for fetal growth restriction or macrosomia, were exclusion criteria. Placental samples were obtained to measure DNA methylation, DNA methyltransferase Dnmt1/3a/3b and demethylase Tet1/2/3, RNA methylation, RNA methyltransferases and demethylases, and m6A RNA reader YTHDF1/3. Data were compared between obese and non-obese women. 12 obese (mean BMI 42.4 [IQR: 35.6-46.6]) and 12 non-obese patients (mean BMI 23.2 [IQR: 22.8-24.1]) have been enrolled. Placental DNA methylation levels were significantly higher in obese subjects. There was no difference of Dnmt1, 3a and 3b mRNA and protein expression between obese and non-obese subjects; however, the DNA demethylases Tet1, 2 and 3 were inhibited by obesity. Obesity reduced m6A levels but did not affect the expression of Mettl3 and Mettl14. Obesity suppressed the expression of key components of the Mettl3-Mettl14-WTAP complex including RBM15, WTAP and KIAA1429. Finally, maternal diabetes repressed the RNA reader YTHDF3, but did not affect the RNA demethylases FTO and ALKBH5. Our study demonstrates that DNA and RNA methylation plays an important role in the regulation of placental gene expression in non-complicated obese pregnancies by showing increased DNA methylation and decreased RNA methylation. These epigenetic findings may help explain the observed differences in perinatal outcomes between obese and non-obese pregnancies.